•Fig. 41.19 RelationshipofGHandIGF-I.GHhasdirectendocrineactionsongrowthandstimulatestheproductionofIGF-I,IGFBP-3andALSintheliver.CirculatingIGF-Iexertsendocrineactionsontargetorgans.IGF-1isalsoproducedlocallyinbone,whereitexertsparacrineeffects.Part,butnotallofthislocalIGF-IproductionisGH-dependent.
GH acts through a specific GH receptor (GHR) that is a member of the cytokine receptor family. A GHR dimer binds to GH, which triggers activation of the JAK/STAT signaling pathway (see
Fig. 41.17 ). This results in phosphorylation of STAT5b, which translocates to the nucleus to stimulate transcription of GH-responsive genes. Additional signaling pathways activated by GH include MAPK and PI3K among others.
In the fed state, GH is a protein anabolic hormone that increases cellular amino acid uptake and incorporation into protein. Consequently it produces nitrogen retention (positive nitrogen balance) and decreases urea production. The muscle wasting that occurs concomitant with aging has been proposed to be caused at least in part by the decrease in GH secretion that occurs during senescence. In children, GH increases skeletal, muscular, and visceral growth; children without GH show growth stunting or dwarfism. GH promotes cartilage growth and both linear and appositional growth of long bones (
Fig. 41.20 , green arrowheads).
Although GH is an effective stimulator of IGF production, this response requires insulin, which supports GH receptor expression and signaling in hepatocytes. When a balanced supply of nutrients is available, high serum glucose levels stimulate insulin secretion and high serum amino acid levels promote GH secretion (
Fig. 41.21, top ). These conditions are appropriate for growth, and GH in turn stimulates IGF-I production by the liver. IGFs are mitogenic and have profound anabolic effects on many organs and tissues, including muscle, cartilage, and bone. Together, GH and IGF-I promote chondrocyte proliferation, differentiation, and hypertrophy during the process of endochondral ossification (see
Fig. 41.20, green arrowheads). After closure of the epiphyses, longitudinal growth ceases but appositional growth of long bones continues. IGF-I stimulates osteoblast replication and synthesis of collagen and bone matrix. Not surprisingly, serum IGF levels correlate well with growth in children. The role of GH changes with alteration of nutritional status. If the diet is high in calories but low in amino acids, for example, high carbohydrate availability promotes insulin secretion but low serum amino acid levels inhibit GH and IGF production (see
Fig. 41.21, middle). These responses allow dietary carbohydrates and fats to be stored, but conditions are unfavorable for growth.
In the fasted state, on the other hand, when nutrient availability wanes, serum GH levels rise and serum insulin levels fall in response to hypoglycemia (see